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The effect of tetrahydrobiopterin (BH4) on diabetic nephropathy

Research Project

Project/Area Number 13670827
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionOsaka City University

Principal Investigator

SHINTAKU Haruo  Osaka City University, Graduate School of Medicine, DEPARTMENT of Pediatrics, Associated Professor, 大学院・医学研究科, 助教授 (00206319)

Co-Investigator(Kenkyū-buntansha) KAWAMURA Tomoyuki  Osaka City University, Graduate School of Medicine, DEPARTMENT of Pediatrics, Assistant, 大学院・医学研究科, 助手 (60271186)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2003: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Keywordstetrahydrobiopterin / diabetes mellitus / endothelial NOS / nitric oxide / type 2 diabetes / biopterin / GTP cyclohydolase / dihydorpteridine reductase
Research Abstract

Nitric oxide synthase (NOS) requires tetrahydrobiopterin (BH4) as a coenzyme. Recent works showed that NOS activity is regulated in a BH4-dependent manner. Nitric oxide (NO) synthesis and metabolism are impaired in blood vessels of diabetic subjects. The concentration of BH4 is low in diabetic rats, probably contributing to endothelial dysfunction. If diabetic kidneys had such deficiency, it might cause nephropathy. The object of this research was to clarify anti-nephropathic effects of BH4 in diabetes meritus.
We studied in streptozotocin (STZ) induced diabetic rats as a model of type 1 diabetes. Spargue-Dawley rats were divided by three groups, Control, STZ, STZ+BH4. BH4 was administered orally at 20mg/kg BW daily. STZ group had albuminuria at 9-week, and developed diabetic nephropathy until 14-week. But STZ+BH4 group did not develop during experiment. The renal expression of eNOS was decreased in STZ group, and this decrease was restored in STZ+BH4 group.
We set out to find if the BH4 … More level in kidneys is low and, if so, whether it is involved in proteinuria. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, with a model of type 2 diabetes, and used Long-Evans Tokushima Otsuka (LETO) rats as healthy controls. OLETF rats were put into groups with or without daily oral doses of BH4 (10 mg/kg) during the study. We obtained plasma, red blood cells, and kidneys from 62-week-old rats and measured BH4, total biopterin, and GTP cyclohydrolase I activity, the key enzyme of de novo BH4 synthesis. We measured urinary protein excretion in the rats at 13, 37, or 61 weeks of age as a marker of nephropathy and stained their kidneys with anti-eNOS antibodies with an immunofluorescent method. Plasma and renal levels of BH4 and biopterin were lower in diabetic rats than in controls. GTP cyclohydrolase activity of red blood cells and renal tissue from diabetic rats was less than that of controls. The BH4/biopterin ratio was smaller in the diabetic rats, suggesting that dihydropteridine reductase, which recycles BH4 from inactive BH2, has low activity in diabetes. Urinary protein was greater in diabetic rats at 13 weeks than in controls ; the difference increased with age. BH4 suppressed proteinuria in diabetic rats at 37 and 61 weeks without affecting body weight, plasma glucose, or blood pressure. Diabetic kidneys had less fluorescence from anti-eNOS antibodies than control kidneys, unless BH4 was given. In this model of diabetes, little BH4 was synthesized, apparently because of GTP cyclohydrolase and dihydropteridine reductase activities were low. Deficiencies of BH4 and of the eNOS-NO system may contribute to the progression of diabetic nephropathy. These results suggest that BH4 seems to have anti-nephropathic effects and may preYent progress of diabetic nephropathy. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] H.Shintaku: "The Effect Of Tetrahydrobiopterin (Bh4) On Diabetic Nephropathy In Streptozotocin (Stz) Induced Diabetic Rats"Chemistry and Biology of Pteridines and Folates 2001. 355-358 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Kimura: "The Peptides Specific Cytotoxity of T lymphocytes against GAD and Insulin in Type I Diabates Patients"Diabetes Research and Clinical Practice. 51. 173-179 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] H.Shintaku: "Long-Term Treatment and Diagnosis of Tetrahydrobiopterin-Responsive Hyperphenylalaninemia with a Mutant Phenylalanine Hydroxylase Gene."Pediatr Res.. 55. 425-430 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwanaga N: "Activity of synthetic enzymes of tetrahydrobiopterin in the human placenta."Int J Mol Med. 13(1). 117-120 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iino T: "Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members."Arch Biochem Biophys. 416(2). 180-187 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] H.Shintaku: "Pterins, Folates and Neurotransmitters in Molecular Medicine"SPS publications. 219 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shintaku H, et al.(edts.S.Milstein): "The effect of tetrahydrobiopterin (BH4) on diabetic nephropathy in streptozotocin(stz) induced diabetic rats"Chemistry and Biology of Pteridines and Folates 2001 (Kluwer Academic Publishers, Massachusetts). 355-358 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Kimura, et al.: "The Peptides Specific Cytotoxity of T lymphocytes against GAD and Insulin in Type I Diabates Patients"Diabetes Research and Clinical Practice. 51. 173-179 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shintaku H, et al.: "Long-Term Treatment and Diagnosis of Tetrahydrobiopterin-Responsive Hyperphenylalaninemia with a Mutant Phenylalanine Hydroxylase Gene"Pediatr Res. 55. 425-430 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwanaga N, et al.: "Activity of synthetic enzymes of tetrahydrobiopterin in the human placenta"Int J Mol Med. 13. 117-120 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iino T, et al.: "Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members"Arch Biochem Biophys. 416. 180-187 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shintaku H, et al.(edts.RA.Levine, N.Blau): "Tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene"Pterins, Folates and Neurotransmitters in Molecular Medicine (Kluwer Academic Publishers, Boston, Dordrecht, London). 141-145 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] H.Shintaku: "Long-Term Treatment and Diagnosis of Tetrahydrobiopterin-Responsive Hyperphenylalaninemia with a Mutant Phenylalanine Hydroxylase Gene"Pediatr Res.[Epub ahead of print]. Dec 17. (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwanaga N: "Ishiko O : Activity of synthetic enzymes of tetraphydrobiopterin in the human placenta"Int J Mol Med. 13(1). 117-120 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iino T: "Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members"Arch Biochem Biophys. 416(2). 180-187 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawamura T: "Cerebrovascular disease and diabetic patients with hypertension"Nippon Rinsho. 61(7). 1175-1180 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Shintaku: "Tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene"Pterins, Folates and Neurotransmitters in Molecular Medicine. 141-145 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujioka H: "Role of nitric oxide synthase and tetrahydrobiopterin in hypoxicischemic encephalopathy in neonatal period"Pterins, Folates and Neurotransmitters in Molecular Medicine. 88-91 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 新宅治夫: "小児疾患診療のための病態生理2"ビオプテリン代謝異常症. 1420 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Shintaku: "The Effect Of Tetrahydrobiopterin (Bh4) On Diabetic Nephropathy In Streptozotocin (Stz) Induced Diabetic Rats"Chemistry and Biology of Pteridines and Folates 2001. 355-358 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Shintaku: "Tetrahydrobiopterin Responsive Hyperphenylalaninemia Without Biopterin Deficiency"Chemistry and Biology of Pteridines and Folates 2001. 301-304 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Shintaku: "The Effect Of Tetrahydrobiopterin (Bh4) On Sperm Motility"Chemistry and Biology of Pteridines and Folates 2001. 345-348 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Shintaku: "Disorders of tetrahydrobiopterin metabolism and their treatment"Curr Drug Metab. 3(2). 123-131 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川村智行: "1型糖尿病のインスリン療法の多様性"小児内科. 34. 1625-1629 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川村智行: "小児期1型糖尿病に対するインスリンリスプロの使用症例"Diabetes Frontier. 14. 94-100 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Shintaku: "The Effect Of Tetrahydrobiopterin (Bh4) On Diabetic Nephropathy In Streptozotocin (Stz) Induced Diabetic Rats"Chemistry and Biology of Pteridines and Folates 2001. (in press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Shintaku: "Tetrahydrobiopterin Responsive Hyperphenylalaninemia Without Biopterin Deficiency"Chemistry and Biology of Pteridines and Folates 2001. (in press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Shintaku: "The Effect Of Tetrahydrobiopterin (Bh4) On Sperm Motility"Chemistry and Biology of Pteridines and Folates 2001. (in press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Kimura: "The Peptides Specific Cytotoxity of T lymphocytes against GAD and Insulin in Type I Diabates Patients"Diabetes Research and Clinical Practice. 51. 173-179 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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